This invention relates to the use of biologically reversible protective groups in medicinal chemistry. More particularly, it relates to providing ionic phosphate and phosphonate compounds intracellularly in biological systems through the use of biologically reversible protective groups.
Bioreversible protective groups and their uses are well-known in medicinal chemistry. Some compounds that are potentially useful in biological systems cannot be directly provided in those systems, because they will be rapidly decomposed or are otherwise incompatible with that biological environment in a way that renders them ineffective. However, when this type of compound is derivatized with protective groups, the composite product usually has different physical and chemical properties that the parent. These modified properties can make the product suitable for introduction into certain biological environments that its parent is not. If the protective groups are later removed under biological conditions, the parent compound is left to perform its useful function.
This general method has a number of applications. For example, if the parent is unstable under the relevant biological conditions, it can be derivatized with protective groups which will create a more stable product. The protective groups can be selected so that they will be removed under predetermined biological conditions that exist at the site in the system where the parent is needed.
One area where this concept has apparently not yet been applied with satisfactory results is in the manipulation of phosphate and phosphonate compounds. These compounds, particularly phosphomonoesters and phosphodiesters, play a key role in cellular metabolism. They are involved in almost every metabolic sequence, including the synthesis of carbohydrates, lipids, amino acids, proteins, nucleotides and nucleic acids. One logical way to regulate these metabolic processes is to inhibit intracellular phosphate metabolizing enzymes by using structurally analogous phosphates. These phosphoesters have very substantial therapeutic potential, but thus far they have not been practically useful, because they usually cannot penetrate cell membranes.
There are two reasons for this penetration problem. First, these phosphoesters are negatively charged at physiologic pH and are highly hydrophilic. Consequently, they are chemically incompatible with lipid membranes. Second, most of these compounds are rapidly degraded by enzymes in the blood and on cell surfaces.
As an example, most purine and pyrimidine antimetabolites used in the treatment of cancer require intracellular conversion to the corresponding 5'-mono-, di-, or tri-phosphates in order to exert cytotoxicity. In experimental tumors, resistance to these agents frequently correlates with the deletion or decreased activity of enzymes that convert the administered drugs to the 5'-mononucleotides.
These problems have been recognized since about 1955. A number of attempts have been made to overcome them by using protective groups to change the phosphates into neutral, lipophilic derivatives which could resist the blood and cell surface enzymes. These derivatives would theoretically enter the target cells and then be demasked. This has apparently never been satisfactorily achieved in practice. Prior art masked phosphates have basically proved to be biologically inert. This is believed to be attributable to their failure to demask under biological conditions.
Thus, there remains a need for means to provide useful phosphates and phosphonates intracellularly. For this goal to be achieved through the use of protective groups, the masked phosphate must not be degraded by blood or cell surface enzymes and the protective groups must be removed under the biological conditions that exist in the target cells.